HIV Drug Resistance in the HIV Drug Resistance in the AsiaAsia-- PacificPacific

David A CooperDavid A CooperNational Centre in HIV Epidemiology National Centre in HIV Epidemiology

and Clinical Researchand Clinical ResearchThe University of New South WalesThe University of New South Wales

Sydney, AustraliaSydney, Australia

•• Transmitted resistanceTransmitted resistance

•• Resistance to firstResistance to first--line therapyline therapy

•• TREAT AsiaTREAT Asia-- response to resistanceresponse to resistance

•• SECOND LINESECOND LINE

HIVDR in Asia PacificHIVDR in Asia Pacific

•• Transmitted resistanceTransmitted resistance

•• Resistance to firstResistance to first--line therapyline therapy

•• TREAT AsiaTREAT Asia-- response to resistanceresponse to resistance

•• SECOND LINESECOND LINE

HIVDR in Asia PacificHIVDR in Asia Pacific

HIV drug resistance survey method criteria•Standard procedures should be specified so that results will be comparable from country to country over time

• The survey methods should be simple and require minimal resources

• Surveys should focus on small geographic areas

• The method should maximise the likelihood that participants will have been infected with HIV within the past 3 years and limit the likelihood of previous ART exposure

• The required sample size should be small

• Specimen collection and handling procedures must be feasible in areas with minimal laboratory resources

• Definition of transmitted resistance should be based on a list of resistance mutations developed and regularly updated as new data become available

HIVDR in Asia PacificHIVDR in Asia Pacific-- Transmitted ResistanceTransmitted Resistance

Bennett et al., Antivir Ther 2008:13 Suppl 2.

Participant eligibility criteria for HIVDR threshold surveysMandatory criteria

•Laboratory confirmation of HIV infection

•Age 500 copies/ml

HIVDR in Asia PacificHIVDR in Asia Pacific-- Transmitted ResistanceTransmitted Resistance

Bennett et al., Antivir Ther 2008:13 Suppl 2.

Site selection criteria for HIV drug resistance threshold surveysMandatory criteria- At least 50-70 specimens expected in 3-6 months

- Every eligible person likely to be included

- All individuals receive a routine HIV test, or

- Specimens from other tested routinely tested as part of anonymous survey, or

- Uptake of optional HIV tests is >95%

- Persons diagnosed with HIV are representative of the area

- Sufficient records to exclude a 2nd positive test

- Opportunity to provide remnant or second blood sample for testing

- Confidentiality safeguards

- Informed consent procedures possible

Recommended criteria- Information on previous HIV tests available

- Information on CD4 count, WHO stage and ART eligibility recorded

- Site is part of national system that identifies previous HIV diagnosis and ART use

HIVDR in Asia PacificHIVDR in Asia Pacific-- Transmitted ResistanceTransmitted Resistance

Bennett et al., Antivir Ther 2008:13 Suppl 2.

Summary of drug resistance threshold surveys in Asia-PacificCountry Site type Number Sequenced Predominant

HIV subtypeTransmitted resistance

Malaysia1 HIV clinic 100 100 CRF01_AE 1 case (NNRTI)

Thailand2 HIV clinic 305 305 7 cases(RT)

Thailand3 Blood donor/ VCT

100 84 CRF01_AE No cases

Vietnam4 VCT 70 44 CRF01_AE 1 case

Thailand5 HIV clinic 113 113 CRF01_AE 14 cases (NRTI)

1 Tee et al., AIDS Res Hum Retroviruses, 2006: 22(2).2 Apisarnthanarak et al., HIV Med, 2008: 9. 3 Sirivichayakul et al., Antivir Ther, 2008: 13 Suppl 2.4 Nguyen et al., Antivir Ther, 2008: 13 Suppl 2.5Sukasem et al., Int J Antimicrob Agents, 2008: 31.

HIVDR in Asia PacificHIVDR in Asia Pacific-- Transmitted ResistanceTransmitted Resistance

•• Transmitted resistanceTransmitted resistance

•• Resistance to firstResistance to first--line therapyline therapy

•• TREAT AsiaTREAT Asia-- response to resistanceresponse to resistance

•• SECOND LINESECOND LINE

HIVDR in Asia PacificHIVDR in Asia Pacific

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Evaluation of WHO criteria for ART failure

Test Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

CD4 cell count failure at 12 months 21.2 95.8 36.8 91.3

- with results from 6-month visit 21.2 90.6 20.6 90.9

WHO-defined clinical failure 15.2 88.1 12.8 90.0

- excluding TB 12.1 90.6 12.9 89.9

- excluding >10% weight loss 9.1 93.0 13.0 89.9

CD4 cell count (12 months) or WHO- defined clinical failure

33.3 85.6 21.2 91.8

Clinical failure due to TB 3.0 96.5 9.1 89.6

Cohort of 324 participants with treatment failure from South Africa

Mee et al., AIDS 2008:22.

Summary of genotypic resistance at virological failure 48 weeks after start of first-line therapy

- from 20 studies in developed countries

- incorporating 7970 patients

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Adapted from Gupta et al., CID 2008:47.

Number of major reverse transcriptase codon mutations (%)

Mutation B-strain (n=14)

CRF01_AE (n=29)

Total (n=43)

M41L 3 (21.4) 3 (10.3) 6 (14.0)D67N 3 (21.4) 5 (17.2) 8 (18.6)K70R 2 (14.3) 1 (3.4) 3 (7.0)

M184V 5 (35.7) 9 (31.0) 14 (32.6)L210W 4 (28.6) 7 (24.1) 11 (25.6)

T215Y/S 5 (35.7) 6 (20.7) 11 (25.6)K129Q/E 3 (21.4) 6 (20.7) 9 (20.9)

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Development of HIVDR after PI-based first-line regimen in Thailand

Sukasem et al., Int J Antimicrob Agents 2008:31

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Drug resistance mutations by viral load at failure

Sungkanuparph et al., CID 2007:44

http://www.journals.uchicago.edu/action/showFullPopup?doi=10.1086/510745&id=_e3

Genotypic drug resistance in 1,880 HIV patients experiencing treatment failure in Thailand 2000-2005

Num

ber o

f res

ista

nt is

olat

es

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Sukasem et al., Infection 2007:35

NRTI NNRTI PI

1000

800

600

400

200

0

3TCAZTzacitabineddId4Tabacavirtenofovirfoscanet

nevirapinedelavirdineefavirenz

nelfinavirsaquinavirindinavirritonaviramprenaviratazanavirlopinavir-ritonavir

HIVDR in Asia PacificHIVDR in Asia Pacific-- Resistance to firstResistance to first--line therapyline therapy

Multivariate analysis of variables associated with virological failure and at least 1 major drug resistance mutation in South Africa

Marconi et al., CID 2008:46

No significance seen in univariate analysis of sex; employment; recent symptoms; hemoglobin; WHO clinical stage; treatment adhere; traditional medicine use; d4T+3TC vs ZDV+3TC or prior vs first HAART.

•• Transmitted resistanceTransmitted resistance

•• Resistance to firstResistance to first--line therapyline therapy

•• TREAT AsiaTREAT Asia-- response to resistanceresponse to resistance

•• SECOND LINESECOND LINE

HIVDR in Asia PacificHIVDR in Asia Pacific

TREAT Asia Studies to Evaluate Resistance (TASER)Objectives:

- evaluate HIVDR and build capacity for surveillance and monitoring of HIVDR in Asia

TASER-monitoring (TASER-M)

- assess prevalence of HIVDR in individuals initiating first- line therapy, and incidence of HIVDR at 12 months after initiation

- assess prevalence and incidence of HIVDR in individuals switching to second-line therapy

TASER-surveillance (TASER-S)

- assess prevalence of transmitted HIVDR in ART-naïve recently HIV-infected individuals

HIVDR in Asia PacificHIVDR in Asia Pacific-- TREAT AsiaTREAT Asia

LAASER Activity Plan, 2007

HIVDR in Asia PacificHIVDR in Asia Pacific-- TREAT AsiaTREAT Asia

TREAT Asia Quality Assurance Scheme (TAQAS)The goal of the TAQAS is to standardize and optimise the outcome of HIV genotyping among sequencing platforms and laboratories

• Panels (3 plasma and 1 electropherogram) were sent to the 15 participating laboratories (13 Asian, 1 South African and 1 North American)

• Each laboratory carried out genotypic analysis and sent he results for external quality assessment

• Nucleotide sequences and ARV susceptibility profiles generated by the participants were compared.

Level of agreement (%) in interpretation of ARV susceptibility between participants using

TAQAS Panel Various systems Stanford Database

1* 71 97

2* 64 95

3 76 83

4 ND 80

HIVDR in Asia PacificHIVDR in Asia Pacific-- TREAT AsiaTREAT Asia

Land et al., 17th IAS, 2008, Mexico City

*Chi-squared p

•• Transmitted resistanceTransmitted resistance

•• Resistance to firstResistance to first--line therapyline therapy

•• TREAT AsiaTREAT Asia-- response to resistanceresponse to resistance

•• SECOND LINESECOND LINE

HIVDR in Asia PacificHIVDR in Asia Pacific

• Currently no evidence available• the default position is “give PI/r +

2NRTIs”• this is OK in developed countries

• close monitoring, numerous options

• this will not work in developing countries• clinical +/- CD4 monitoring only• presence of multiple resistance mutations• limited options• 3rd line cART is unlikely for public-sector funding in the

short- to medium-term

HIVDR in Asia PacificHIVDR in Asia Pacific-- SECOND LINESECOND LINE

• RCT of patients failing NNRTI+2NRTIs• randomization:

• PI/r + 2NRTIversus

• PI/r + raltegravir• 96-week trial

• 48-week analysis for public disclosure• 1o endpoint: proportion

• powered for non-inferiority (15% CIs)• 480 patients• Australia and UK

• 10% enrolment

• Africa, India, SE Asia, Latin America• 90% enrolment

• 3-4 years drug supply• 1-2 years post-trial depending on country

HIVDR in Asia PacificHIVDR in Asia Pacific-- SECOND LINESECOND LINE

• requests of pharmaceutical sponsors:• raltegravir and boosted-PI supply

- 3-4 years- 2 years study and 1-2 years post study

• partial financial support shared with other sponsors

- a Public-Private Partnership model

• NCHECR/UNSW• trial sponsor and study coordination

• trial management• representatives from trial sponsor, industry partners, other

funders and a PI from each region/country participating

HIVDR in Asia PacificHIVDR in Asia Pacific-- SECOND LINESECOND LINE

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